This is a resubmission of the Collaborative Genetic study of Nicotine Dependence (COGEND), a new five-year Program Project Grant to detect and evaluate familial and non-familial causes of nicotine dependence. The goals of the program are the identification of biological mechanisms, genes and environmental features that determine nicotine consumption and predispose or protect individuals from the onset and persistence of the disorder. Improved understanding of these factors will suggest novel, powerful strategies for reducing or eliminating nicotine dependence and the massive health burden it places on all societies. Subjects and families will be recruited from comparable HMOs at three sites; The Henry Ford Hospital (Detroit), The University of Minnesota (Minneapolis-St. Paul) and Washington University (St. Louis). There are three interrelated studies: (1) a genetic epidemiology study of the families of nicotine dependent individuals, (2) a genetic linkage and candidate gene study of nicotine of nicotine dependence and related phenotypes and (3) a neuropharmacology study of the relationship between nicotine dependence and related phenotypes and (3) a neuropharmacology study of the relationship between nicotine metabolism and tobacco consumption and dependence. Candidate gene studies include case- control and family based designs to maximize power and minimize bias due to ethnic stratification. African-Americans will be over-sampled to provide a sufficient sample for statistical consumption, nicotine metabolism and assessment of familial and non-familial variables in multiple domains that are correlated with the disorder. Data management and administrative cores support these studies. Each project contributes thematically to the program. The family epidemiology project elucidates environmental and familial factors from which informative quantitative and qualitative phenotypes are derived. The linkage and candidates gene studies include a genome-wide survey, fine mapping and case-control and family based candidate gene studies to identify genes that determine nicotine consumption, and susceptibility or protection from nicotine dependence. Their effect on the incidence and familial distribution of nicotine dependence and tobacco consumption will be studied in the large of probands, controls and relatives metabolism providing biological insight into disorder and endophenotypes and candidate genes for the genetic study. Metabolic variables will be used as co-variables in the family, population and linkage studies. A team of investigators from three centers will work together to unravel this disorder. Our team includes epidemiologists, geneticists, statisticians, psychiatrists, psychologists, and pharmacologists. We hope to translate these basic biological and environmental studies into strategies to reduce the massive health burden of nicotine dependence.